Abstract A061: A cost-effective two-step approach for multi-cancer early detection in general population

Abstract In population-wide cancer screening, three key issues need to be focused on: number of cancer cases identified, the issue of false positives, and cost. A high false positive rate can result in a significant waste of healthcare resources. Large-scale screening inevitably leads to significant financial burdens on the healthcare system which is a key factor constraining nationwide screening. OncoSeek is a multi-cancer early detection (MCED) test using a panel of seven plasma protein tumor markers (PTMs) and artificial intelligence (AI). SeekInCare is a MCED test that integrates the seven PTMs and four cancer genomic features (aneuploidy, fragment size, end motifs, and oncogenic viruses) from cell-free DNA (cfDNA) by shallow whole-genome sequencing (sWGS). In a two-step approach, the initial screening is conducted using OncoSeek and SeekInCare is then used as the secondary test for those individuals who tested positive by OncoSeek. In a case-control study (n = 1197) including both OncoSeek and SeekInCare testing results, OncoSeek showed 49.9% sensitivity at 91.0% specificity, while SeekInCare demonstrated 60.0% sensitivity at 98.3% specificity. In the two-step process, specificity significantly increased from 91.0% to 99.3%, while sensitivity decreased from 49.9% to 39.9%. We modeled a screening in five million adults aged ≥ 50 years with a cancer incidence rate of 1.9%. The simulated real-world sensitivities of OncoSeek and two-step were adjusted downward proportionally to 28.0% and 22.4% based on the sensitivity differences observed between GRAIL’s CCGA study (case-control, 51.5%) and PATHFINDER study (prospective, 28.9%). While at 91.0% specificity OncoSeek had 441,450 cases of false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although Galleri ($949 per test) identified more cancer cases than the two-step MCED, with 27,455 and 21,280 cases respectively, its total cost for the former reached $4,745 million. As the positive predictive value (PPV) of two-step (38.3%) was the same as Galleri (38.3%), it reduced cost 6.6-fold, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected using Galleri is $172,828 compared to $33,534 using the two-step MCED, which represents a 5.2-fold difference. In conclusion, the two-step approach not only significantly reduces false positives, but also cuts the screening cost down substantially, making it a cost-effective strategy for population-wide cancer screening. Citation Format: Mao Mao, Geng shuai peng, Li shi yong, Wu Wei, Chang Yin Yin. A cost-effective two-step approach for multi-cancer early detection in general population [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A061.